Metabolic Disorders
Millions of people throughout the world are affected daily by metabolic disorders such as obesity, anorexia, cachexia, and diabetes. Though the causes for these disorders are as varied as the disorders themselves, many candidate genes and gene products, such as insulin, leptin, and ghrelin, have been identified as potential drug targets for treatment of these disorders. However, these disorders have yet to be conquered.
Obesity, Anorexia, Cachexia, and Diabetes
Understanding metabolic disorders has been hampered by the absence of an animal model that immediately reflects the human situation. Human metabolic disorders do not generally follow a Mendelian inheritance pattern, wherein a single gene determines a metabolic disorder phenotype (physical manifestation of a gene's expression; Weigle and Kuijper, 1996), although there are several rodent models that do (Spiegelman and Flier, 1996; Weigle and Kuijper, 1996). Human metabolism is a quantitative trait that, along with environmental and behavioral aspects, is responsible for metabolic activities and disorders (Clement et al., 1998; Montague et al., 1997; Comuzzie and Allison, 1998; Hill and Peters, 1998).
Obesity is an excess of subcutaneous fat in proportion to lean body mass, relating to calorie intake and use. Anorexia is a prolonged loss of appetite whereas cachexia is a general physical wasting and malnutrition usually associated with chronic disease, such as certain types of cancers or HIV. Diabetes, another type of metabolic disorder, is a variable disorder of carbohydrate metabolism caused by a combination of hereditary and environmental factors and usually characterized by excessive urine production and excessive amounts of sugar in the blood and urine, as well as by thirst, hunger and loss of weight. Underlying metabolic dysfunctions contribute substantially to all of the aforementioned metabolic disorders.
Fasting and Feeding Experimental Models
While there are many known candidate genes that may contribute to metabolic disorders (Table 1), other targets for various therapies are desirable. Optimal targets include those genes that are differentially-regulated during fasting and feeding because of their immediate relationship to food intake.
TABLE 1Selected candidate genes for human obesity/body composition (Comuzzieand Allison, 1998)PhenotypeGeneNotesObesityagouti signalingIn mutant (aγ/aγ) mice, agouti is expressedpolypeptideubiquitously (instead of only skin in wild-typemice), and antagonizes melanocyte stimulatinghormone receptor ligation.carboxypeptidaseIn agouti (aγ/aγ) mice, a mutation in thisenzyme prevents processing ofproopiomelanocortin.leptinIn mice, encoded by ob gene; mutanthomozygotes express the obese diabetic (db)mouse phenotype due to aberrant leptintranslational termination.leptin receptorfa/fa (fatty) rats (Phillips et al., 1996)tubby polypeptideMay effect processing of other obesity-relatedpolypeptides: neuropeptide Y and POMC(Aron et al., 1997; Guan et al., 1998;Spiegelman and Flier, 1996; Weigle andKuijper, 1996).proopiomelanocortinKnock-out mice express a phenotype(POMC)resembling that of agouti mutants (Yaswen etal., 1999).tumor necrosis factor-αGenetic linkage study of Pima Indians; up-regulated in adipose tissue in obese people androdents (Norman et al., 1995).Energy balanceuncoupling polypeptidesUncoupling proteins disengage ATP synthesis(1, 2, 3)from mitochondrial respiration, therebyaffecting metabolic rate (Schrauwen et al.,1999).Satietycholecystokinin A and its(CCK) stimulates secretion of digestive enzymereceptorand promotes cell growth (Cancela, 2001).Feedingmelanocortin and itsAppetite suppressants, control feedingbehaviorreceptors (3, 4)behavior, among many other diverse functions(Wikberg et al., 2000).Appetiteneuropeptide YPromote feeding, although knockout miceregulationneuropeptide Y receptorexpressed a weaker phenotype than expected.Double mutant mice, such as ob/ob npy-/npy-have more striking phenotypes (Beck, 2001).ghrelinStimulates feeding and weight gain in mice(Nakazato et al., 2001).other orexinsStimulate feeding, e.g. (Sakurai et al., 1998a;Sakurai et al., 1998b).Adipocyteperoxisome proliferatorAdipogenic transcription factor (Kersten,differentiationactivated receptor-γ2001).β-3-adrenergic receptorExpressed mostly in adipocytes. May becoupled to lipolysis (Strosberg, 1997).
Non-pharmaceutical interventions for treating and controlling metabolic disorders, include diet, exercise, psychiatric treatment and surgery. Pharmaceutical interventions include mostly appetite suppressants and energy expenditure/nutrient-modifying agents. However both forms of treatments are often unsatisfactory, due to either unwanted complications, difficulties in maintaining weight loss after treatment, and/or unwanted side effects. While there are many known candidate genes that may contribute to obesity (Table 1), other targets are desirable. Optimal targets include those genes that are differentially-regulated during fasting and feeding because of their immediate relationship to food intake. These genes, along with their expression regulatory elements and encoded polypeptides represent a class of molecules that are desirable therapeutic targets and are also useful in predicting treatment success by expression profiling.